This invention relates to an improved process for resolving DL-mandelic acid with optically active 2-amino-1-butanol. More particularly, it relates to an improved process wherein higher productivity and improved economics are achieved by the use of more concentrated reaction mixtures, more simplified processing, and very high utilization of key raw materials.
The Applicants are not aware of any prior art references which, in their respective judgments, as persons skilled in the resolution and racemization art, anticipate or render obvious this invention. The publications cited herein may be of assistance in developing the background of this invention and establishing the state of the prior art. The publications are incorporated by reference.
The use of optically active amines to resolve racemic mixtures of carboxylic acids, such as DL-mandelic acid, is well-known. The use of (-)-2-amino-1-butanol to resolve DL-mandelic acid is disclosed by Riedel De Haen AG, West German DT2733-425.
The present invention arose out of research for a more satisfactory process for the resolution of DL-mandelic acid. This research resulted in the discovery of an improved process for the resolution of DL-mandelic acid in water, or a lower aliphatic alcohol, or mixtures thereof, utilizing an optically active 2-amino-1-butanol.
The utility of the products of the improved process of the present invention, D-(-)-mandelic acid, and its derivatives is known. See, e.g., Germ. Offen. 2,415,402 and Germ. Offen. 2,436,686, and English language abstract of which is disclosed in Chem. Abs. 82, 31343m (1975) and Chem. Abs. 83, 10556p (1976), respectively.
In accordance with the present invention, there is provided an improvement in a process for resolving DL-mandelic acid. The known process for resolving L-mandelic acid comprises: (a) reacting DL-mandelic acid with optically active 2-amino-1-butanol in water, in a lower aliphatic alcohol or in a mixture thereof, at a temperature of about 20.degree. to 60.degree. C., to form an optically active mandelate salt represented by formula (I) ##STR1## (b) cooling and recovering the optically active mandelate salt; (c) mixing the mandelate salt with water, and distilling off any residual alcohol at a temperature of about 50.degree. to 90.degree. C.; (d) acidifying the alcohol-free mixture with a mineral acid; and (e) cooling and recovering optically active mandelic acid. The improvement in the process comprises:
(1) recycling the mother liquor of step (b) into step (a) until the mother liquor becomes saturated with the diasteromeric isomer of the mandelate salt; PA1 (2) (i) heating the mother liquor with an alkalizing agent to obtain a racemic solution; or PA1 (ii) heating a mixture consisting essentially of an optically active 2-amino-1-butanol, an optically active mandelic acid, and an alkalizing agent, substantially in the absence of any other solvent, containing the DL-mandelic acid and an optically active 2-amino-1-butanol. PA1 (3) neutralizing the racemic solution with a mineral acid, a mineral acid salt of optically active 2-amino-1-butanol, or a mineral acid salt of optically active 2-amino-1-butanol and mandelic acid, in a lower aliphatic alcohol, to precipitate an alklai or alkaline earth metal salt; PA1 (4) separating the metal salt; PA1 (5) recycling the mother liquor of step (4) into step (a); and PA1 (6) recycling the mother liquor of step (e) into step (c) until the mother liquor becomes saturated with a mineral acid salt of optically active 2-aminio-1butanol and mandelic acid. PA1 (7) heating the saturated mother liquor of step (6) to remove water; PA1 (8) dissolving the residue of step (7) in a lower aliphatic alcohol; and PA1 (9) recycling the solution of step (8) into step (3). PA1 (a) heating an optically active 2-amino-1-butanol mandelate and an alkalizing agent in a lower aliphatic alcohol or alcohol mixture, or a lower aliphatic alcohol and water until racemization is essentially complete; PA1 (b) neutralizing the resulting solution with a mineral acid or a mineral acid salt of 2-amino-1-butanol and mandelic acid in the lower aliphatic alcohol or alcohol mixture to precipitate an alkali or alkaline earth metal salt; PA1 (c) separating the metal salt; and PA1 (d) recovering the resulting solution of DL-mandelic acid.
By "lower aliphatic" is meant a straight or branched open-chain radical containing one to about six carbon atoms. A lower alkyl alcohol is preferred. By "lower alkyl" is meant a saturated straight or branched open-chain radical containing one to about six carbon atoms.
In a preferred embodiment, the improvement in the process comprises the additional steps of:
In an alternative embodiment to the improvement, and to the preferred embodiment of the improvement, the optically active 2-amino-1-butanol in step (a) is (-)-2-amino-1-butanol the alcohol in steps (a) and (3) and in step (8) of the preferred embodiment is methanol; the alkalizing agent in step (2) is potassium hydroxide; the mineral acid salt in step (3) is (-)-2-amino-1-butanol hydrochloride; and the mineral acid salt and mandelic acid in step (6) are (-)-2-amino-1-butanol hydrochloride and D-(-)-mandelic acid. Preferably, the racemic solution in step (3) is neutralized with (-)-2-amino-1-butanol hydrochloride and optically active mandelic acid. More preferably, the mandelic acid is D-(-)-mandelic acid.
In another alternative embodiment to the improvement, and to the preferred embodiment of the improvement, the optically active 2-amino-1-butanol in step (a) is (+)-2-amino-1-butanol the alcohol in steps (a) and (3) and in step (8) of the preferred embodiment is methanol; the alkalizing agent in step (2) is potassium hydroxide; the mineral acid salt in step (3) is (+)-2-amino-1-butanol hydrochloride; and the mineral acid salt and mandelic acid in step (6) are (+)-2-amino-1-butanol hydrochloride and L-(+)-mandelic acid. Preferably, the racemic solution in step (3) is neutralized with (+)-2-amino-1-butanol hydrochloride and an optically active mandelic acid. More preferably, the mandelic acid is L-(+)-mandelic acid.
The improved process of the present invention for the resolution of DL-mandelic acid is more productive than the processes of the prior art and obviates the preparation of optically active 2-benzylamino-1-butanols.
In accordance with the present invention, there is also provided a process for preparing a solution of mandelic acid. This process consists essentially of:
In one embodiment, the alkalizing agent is potassium hydroxide, the lower alcohol is methanol and the mineral acid is hydrogen chloride.
In another embodiment, the alkalizing agent is potassium hydroxide, the lower alcohol is methanol and the mineral acid salt and mandelic acid are (-)-2-amino-1-butanol hydrochloride and D-(-)-mandelic acid.
In yet another embodiment, the alkalizing agent is potassium hydroxide, the lower alcohol is methanol and the mineral acid salt and mandelic acid is (+)-2-amino-1-butanol hydrochloride and L-(+)-mandelic acid.
The process of the present invention for the preparation of a solution of DL-mandelic acid is unique in that the racemization of the optically active mandelic acid is carried out in the presence of an optically active 2-amino-1-butanol that is resistant to racemization under the conditions employed. This results in increased productivity because the separation of the optically active 2-amino-1-butanol and the other optical isomer of mandelic acid is avoided. Also, the optically active 2-amino-1-butanol and the other optical isomer of mandelic acid are essentially 100% recycled.